Use of GLP-1 receptor agonists for the treatment of short bowel syndrome

ABSTRACT

The present invention describes the methods of using incretin mimetics such as GLP-1 receptor agonists, particularly exenatide, to treat short bowel syndrome and spastic or hyperactive esophageal motor disorders.

This application is the National Phase of International ApplicationPCT/US08/61417, filed Apr. 24, 2008, which designated the U.S. and thatInternational Application was published under PCT Article 21(2) inEnglish. This application also includes a claim of priority under 35U.S.C. §119(e) to U.S. provisional patent application No. 60/914,687,filed Apr. 27, 2007, and U.S. provisional patent application No.60/915,901, filed May 3, 2007.

FIELD OF INVENTION

This invention relates to the use of GLP-1 receptor agonists to treatshort bowel syndrome and spastic or hyperactive esophageal motordisorders.

BACKGROUND

All publications herein are incorporated by reference to the same extentas if each individual publication or patent application was specificallyand individually indicated to be incorporated by reference. Thefollowing description includes information that may be useful inunderstanding the present invention. It is not an admission that any ofthe information provided herein is prior art or relevant to thepresently claimed invention, or that any publication specifically orimplicitly referenced is prior art.

One gastrointestinal disorder is short bowel syndrome (SBS), alsoreferred to as small intestine insufficiency. SBS is a serious, oftenlife-threatening, medical problem resulting in severe diarrhea andnutritional deprivation. Injury or trauma may cause short bowelsyndrome; for example, surgical removal of a large portion of the smallintestine. The removal may result in the lack of surface area in theremaining bowel to absorb enough nutrients from food. Short bowelsyndrome may also be caused by the small intestine's loss of absorptivefunction due to diseases; for example, Crohn's disease and cancer.Though rare, short bowel syndrome may be congenital and is oftenreferred to as Congenital Short Bowel Syndrome.

Other symptoms of short bowel syndrome include, but are not limited toabdominal pain, steatorrhoea, greasy stools, edema, weight loss, andfatigue. The symptoms result from a lack of absorptive surface and lossof the braking mechanisms controlling the proximal gut. One of themissing, distally produced, peptides that control the proximal gut isglucagon-like peptide-1 (GLP-1). Complications due to short bowelsyndrome include weight loss, malnutrition, weakened bones, gallstones,bacterial overgrowth, metabolic acidosis and kidney stones.

Currently available treatments for short bowel syndrome aim to relieveits symptoms. A high-calorie and low-residue diet may be prescribed.Medications attempt to lengthen the time the nutrients are available inthe intestine for absorption. In instances wherein normal feeding is notdelivering enough nutrients, parenteral nutrition may be necessary.Surgery, such as intestinal lengthening or tapering, may be performed.

Currently, there is no cure for short bowel syndrome and treatmentoptions are not completely effective for all patients. Thus, there is aneed in the art for alternative or improved methods and compositions totreat short bowel syndrome.

Other gastrointestinal disorders include spastic or hyperactiveesophageal motor disorders which may limit the delivery of food andliquid, as well as cause painful symptoms. Examples of spastic orhyperactive esophageal motor disorders include, but are not limited to,esophageal spasms, nutcracker esophagus and achalasia.

Esophageal spasms are uncoordinated series of muscle contractions thatprevent the proper traveling of food into the stomach. Some signs andsymptoms of esophageal spasms include chest pain, difficulty swallowing,painful swallowing, a sensation that an object is stuck in the throat,regurgitation, and heartburn. Short term treatment of esophageal spasmsmay involve the use of medications to relax the esophageal muscles. Longterm treatment of esophageal spasms may include management of anycontributing health condition (e.g., gastroesophageal reflux disease(“GERD”)), medications, and alteration of eating habits.

Nutcracker esophagus is an abnormality wherein swallowing contractionsare too powerful. Symptoms of nutcracker esophagus include chest pain,dsyphagia, and heartburn. Treatment options for nutcracker esophagusinclude anti-reflux therapy to treat an underlying cause (e.g., GERD),use of medications such as nitrates or calcium channel blockers to relaxthe esophageal and stomach muscles, and use of tricyclic antidepressantsto lower the pain sensation.

Achalasia is an esophageal disorder wherein the esophagus is less ableto move food towards the stomach and the muscle from the esophagus tothe stomach does not relax as much as it needs to be during swallowing.Symptoms of achalasia include difficulty swallowing liquids and solids,regurgitation of food, chest pain, weight loss, heart burn and cough.Current treatment for achalasia seeks to reduce the pressure at thelower esophageal sphincter; for example, widening of the loweresophageal sphincter or injecting the lower esophageal sphincter withbotulimun toxin to paralyze it and prevent spasms. Long-acting nitratesand calcium channel blockers may also be used to lower the pressure ofthe lower esophageal sphincter. Complications of achalasia may includeperforation of the esophagus, reflux, and aspiration of food into thelungs.

However, anti-reflux medications only reduce a risk factor for theseconditions; medications to relax the muscles only provide relief to somepatients and their effectiveness overall is not very good; and the useof antidepressants only treats the associated pain, rather than theabnormalities themselves. Thus, there exists a need in the art foralternative and/or additional treatments for spastic or hyperactiveesophageal motor disorders.

SUMMARY OF THE INVENTION

The following embodiments and aspects thereof are described andillustrated in conjunction with compositions and methods which are meantto be exemplary and illustrative, not limiting in scope.

The present invention provides a method for treating a gastrointestinaldisorder in a subject in need thereof, comprising: providing an incretinmimetic; and administering a therapeutically effective amount of theincretin mimetic to the subject. In one embodiment, the incretin mimeticmay be a glucagon-like peptide-1 (GLP-1) receptor agonist. In aparticular embodiment, the GLP-1 receptor agonist may be an exendin.Particularly useful exendins may include exendin-3, exendin-4, andfunctional derivatives thereof. One particularly useful exendin may beexenatide. GLP-1 receptor agonists that may also be used include GLP-1and biologically active forms of GLP-1. In other embodiments, the GLP-1receptor agonist may be a purified polypeptide having an amino acidsequence at least 95% identical to SEQ ID NO: 1. In still otherembodiments, the GLP-1 receptor agonist may be a purified polypeptide asdisclosed by SEQ ID NO: 1 with up to five conservative amino acidsubstitutions.

In various embodiments, the gastrointestinal disorder treated may beselected from the group consisting of short bowel syndrome, spastic orhyperactive esophageal motor disorder, and combinations thereof. Inparticular embodiments, the spastic or hyperactive esophageal motordisorder treated may be selected from the group consisting of esophagealspasm, nutcracker esophagus, achalasia and combinations thereof. In oneparticular embodiment, the gastrointestinal disorder treated may beshort bowel syndrome.

In various embodiments, the therapeutically effective amountadministered may be about 5 micrograms (mcg) to about 10 mcg.Administering may comprise administering the therapeutically effectiveamount twice per day.

The present invention also provides a method of normalizing bowelfunction in a subject in need thereof, comprising: providing an incretinmimetic; and administering a therapeutically effective amount of theincretin mimetic to the subject. Normalizing bowel function may comprisereducing the number of bowel movements in the subject. The incretinmimetic may be a GLP-1 receptor agonist, as noted above. Further, theGLP-1 receptor agonists may be as described herein. The therapeuticallyeffective amount administered may also be about 5 micrograms (mcg) toabout 10 mcg. Further, administering may also comprise administering thetherapeutically effective amount twice per day.

The present invention also provides for a kit for treating agastrointestinal disorder in a subject in need thereof, comprising: anincretin mimetic; and instructions to administer a therapeuticallyeffective amount of the incretin mimetic to the subject. The incretinmimetic may be a GLP-1 receptor agonist as noted above and describedherein. The gastrointestinal disorder treated by the kit may be selectedfrom the group consisting of short bowel syndrome, spastic orhyperactive esophageal motor disorder and combinations thereof.Instructions may include instructions to administer a therapeuticallyeffective amount of an incretin mimetic, and particularly, a GLP-1receptor agonist described herein twice per day.

Other features and advantages of the invention will become apparent fromthe following detailed description, which illustrate, by way of example,various features of embodiments of the invention.

DESCRIPTION OF THE INVENTION

All references cited herein are incorporated by reference in theirentirety as though fully set forth. Unless defined otherwise, technicaland scientific terms used herein have the same meaning as commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. Singleton et al., Dictionary of Microbiology and MolecularBiology 3^(rd) ed., J. Wiley & Sons (New York, N.Y. 2001); and March,Advanced Organic Chemistry Reactions, Mechanisms and Structure 5^(th)ed., J. Wiley & Sons (New York, N.Y. 2001) provide one skilled in theart with a general guide to many of the terms used in the presentapplication.

One skilled in the art will recognize many methods and materials similaror equivalent to those described herein, which could be used in thepractice of the present invention. Indeed, the present invention is inno way limited to the methods and materials described. For purposes ofthe present invention, the following terms are defined below.

“Beneficial results” may include, but are in no way limited to,lessening or alleviating the severity of the disease condition,lessening or alleviating symptoms or complications associated with thedisease condition, preventing the disease condition from worsening,curing the disease condition and prolonging a patient's life or lifeexpectancy.

“Conditions” and “disease conditions” as used herein may include, butare in no way limited to any form of short bowel syndrome and spastic orhyperactive esophageal motor disorders such as esophageal spasms,nutcracker esophagus and achalasia.

“Mammal” as used herein refers to any member of the class Mammalia,including, without limitation, humans and nonhuman primates such aschimpanzees and other apes and monkey species; farm animals such ascattle, sheep, pigs, goats and horses; domestic mammals such as dogs andcats; laboratory animals including rodents such as mice, rats and guineapigs, and the like. The term does not denote a particular age or sex.Thus, adult and newborn subjects, as well as fetuses, whether male orfemale, are intended to be included within the scope of this term.

“Treatment” and “treating” as used herein refer to both therapeutictreatment and prophylactic or preventative measures, wherein the objectis to prevent, reduce the occurrences or lessen the symptoms associatedwith the targeted condition or disease condition even if the treatmentis ultimately unsuccessful. Those in need of treatment include thosealready with the condition or disease condition as well as those proneto have the condition or disease condition or those in whom thecondition or disease condition is to be prevented.

Short Bowel Syndrome

The present invention is based upon the inventors' discovery thatglucagon-like peptide-1 (GLP-1) receptor agonists are useful for thetreatment of short bowel syndrome. In various embodiments, GLP-1receptor agonists may be synthetic or natural exendins such as exendin-3(HSDGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: 2), or exendin-4(HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO 3); insulinotropicfragments of exendin-4 comprising the amino acid sequences:exendin-4(1-31) (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGP; SEQ ID NO: 4) orexendin-4(1-31) (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGY; SEQ ID NO: 5); orfunctional derivatives thereof as described in U.S. Pat. No. 5,424,286,herein incorporated by reference as though fully set forth in itsentirety. The '286 Patent also describes additional GLP-1 receptoragonists that may be appropriate for use in accordance with variousembodiments of the present invention. Additional GLP-1 receptor agonistsand/or exendins and exendin variants that may be appropriate for usewith various embodiments of the present invention include thosedescribed by U.S. Pat. Nos. 6,858,576, 6,872,700, 6,902,744, 6,956,026,7,297,761 herein incorporated by reference as though fully set forth intheir entirety. One particularly useful GLP-1 receptor agonist isexenatide. Exenatide (BYETTA®) is currently marketed by AmylinPharmaceuticals, Inc. and Eli Lilly and Company as adjunctive therapy toimprove glycemic control in patients with type 2 diabetes mellitus.

In various embodiments, methods of treating short bowel syndrome in asubject in need thereof are provided. One method comprises providing aGLP-1 receptor agonist and administering a therapeutically effectiveamount of the GLP-1 receptor agonist to the subject in need of treatmentfor short bowel syndrome. The method may further comprise identifying asubject in need of treatment for short bowel syndrome. Theidentification may be made by any individual, for example, a medicalpractitioner or the subject himself. In a particular embodiment, theGLP-1 receptor agonist is exenatide (e.g., BYETTA® exenatide injection).

Exenatide is a synthetic 39-amino acid peptide amide. Exenatide has theempirical formula C₁₈₄H₂₅₂N₅₀O₆₀S and molecular weight of 4186.6Daltons. The amino acid sequence for exenatide is as follows:H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH₂.(SEQ ID NO: 1).

Exenatide belongs to a class of drugs referred to as incretin mimetics.Thus, another method comprises providing an incretin mimetic andadministering a therapeutically effective amount of the incretin mimeticto a subject in need of treatment for short bowel syndrome. The methodmay further comprise identifying a subject in need of treatment forshort bowel syndrome.

In an alternative embodiment, a naturally produced GLP-1 hormone or abiologically active forms of GLP-1, such as GLP-1-(7-37) andGLP-1-(7-36)NH₂, may be used to treat short bowel syndrome. The methodmay comprise providing a purified quantity of GLP-1 or a biologicallyactive form of GLP-1 and administering a therapeutically effectiveamount of the GLP-1 or the biologically active form of the GLP-1 to asubject with short bowel syndrome to treat the short bowel syndrome.

In another alternate embodiment, a purified polypeptide comprising SEQID NO: 1 may be used to treat short bowel syndrome. Additionally, apurified polypeptide comprising 38, 37, 36, or 35 consecutive residuesof SEQ ID NO: 1 may be used to treat short bowel syndrome. Further, apurified polypeptide with an amino acid sequence comprising a sequenceat least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ IDNO: 1 may be used to treat short bowel syndrome.

In a further embodiment, a purified polypeptide comprising the aminoacid sequence of SEQ ID NO: 1 but with one, two, three, four or fiveconservative amino acid substitutions may be used to treat short bowelsyndrome. A conservative amino acid substitution as used herein refersto a replacement of an amino acid residue with a different residuehaving similar physicochemical characteristics; for example, size,charge and polarity or nonpolarity.

The present invention also provides methods of normalizing bowelfunction in a subject in need thereof. For example, the GLP-1 receptoragonists or the incretin mimetics described above may be used to reducethe number of bowel movements in the subject.

Spastic or Hyperactive Esophageal Motor Disorders

The present invention is also based upon the inventors' discovery thatGLP-1 receptor agonists are useful for the treatment of spastic orhyperactive esophageal motor disorders. Similar to the treatment ofshort bowel syndrome, in various embodiments, GLP-1 receptor agonistsused to treat spastic or hyperactive esophageal motor disorders may beexendins or exendin derivatives as described above. One particularlyuseful GLP-1 receptor agonist is exenatide.

The inventors found that treatment with exenatide reduces esophagealcontraction amplitudes. While not wishing to be bound by any particulartheory, the inventors believe that the reduction in contractionamplitudes is effective for treating spastic or hyperactive esophagealmotor disorders.

In various embodiments, methods of treating a spastic or hyperactiveesophageal motor disorder in a subject in need thereof are provided. Onemethod comprises providing a GLP-1 receptor agonist and administering atherapeutically effective amount of the GLP-1 receptor agonist to thesubject in need of treatment for a spastic or hyperactive esophagealmotor disorder. The method may further comprise identifying a subject inneed of treatment for a spastic or hyperactive esophageal motordisorder. In various embodiments, the spastic or hyperactive esophagealmotor disorder treated by the inventive method may be esophageal spasms,nutcracker esophagus or achalasia. In a particular embodiment, the GLP-1receptor agonist used is exenatide

Another method comprises providing an incretin mimetic and administeringa therapeutically effective amount of the incretin mimetic to a subjectin need of treatment for a spastic or hyperactive esophageal motordisorder. The method may also comprise identifying a subject in need oftreatment for a spastic or hyperactive esophageal motor disorder. Invarious embodiments, the spastic or hyperactive esophageal motordisorder treated with the incretin mimetic may be esophageal spasms,nutcracker esophagus or achalasia.

In an alternative embodiment, a naturally produced GLP-1 hormone or abiologically active forms of GLP-1, such as GLP-1-(7-37) andGLP-1-(7-36)NH₂, may be used to treat the spastic or hyperactiveesophageal motor disorder. The method may comprise providing a purifiedquantity of GLP-1 or a biologically active form of the GLP-1 andadministering a therapeutically effective amount of the GLP-1 or thebiologically active form of the GLP-1 to a subject with a spastic orhyperactive esophageal motor disorder to treat the spastic orhyperactive esophageal motor disorder.

In another alternate embodiment, a purified polypeptide comprising SEQID NO: 1 may be used to treat a spastic or hyperactive esophageal motordisorder. Additionally, a purified polypeptide comprising 38, 37, 36, or35 consecutive residues of SEQ ID NO: 1 may be used to treat a spasticor hyperactive esophageal motor disorder in a subject in need thereof.Further, a purified polypeptide with an amino acid sequence comprising asequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical toSEQ ID NO: 1 may be used to treat a spastic or hyperactive esophagealmotor disorder. In a further embodiment, a purified polypeptidecomprising the amino acid sequence of SEQ ID NO: 1, but with one, two,three, four or five conservative amino acid substitutions may be used totreat a spastic or hyperactive esophageal motor disorder in a subject inneed thereof.

In another embodiment, the present invention also provides a method ofreducing esophageal contraction amplitudes in a subject in need thereof.The method comprises, providing an incretin mimetic or a GLP-1 receptoragonist as described above and administering the incretin mimetic or theGLP-1 receptor agonist to the subject to reduce the esophagealcontraction amplitudes.

In other embodiments, the present invention provides pharmaceuticalcompositions including a pharmaceutically acceptable excipient alongwith a therapeutically effective amount of a GLP-1 receptor agonist oran incretin mimetic. In a particular embodiment, the GLP-1 receptoragonist or incretin mimetic is exenatide. “Pharmaceutically acceptableexcipient” means an excipient that is useful in preparing apharmaceutical composition that is generally safe, non-toxic, anddesirable, and includes excipients that are acceptable for veterinaryuse, as well as for human pharmaceutical use. Such excipients may besolid, liquid, semisolid, or, in the case of an aerosol composition,gaseous.

In various embodiments, the pharmaceutical compositions according to theinvention may be formulated for delivery via any route ofadministration. “Route of administration” may refer to anyadministration pathway known in the art, including but not limited toaerosol, nasal, oral, transmucosal, transdermal, subcutaneous, orparenteral. “Parenteral” refers to a route of administration that isgenerally associated with injection, including intraorbital, infusion,intraarterial, intracapsular, intracardiac, intradermal, intramuscular,intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal,intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous,transmucosal, or transtracheal. Via the parenteral route, thecompositions may be in the form of solutions or suspensions for infusionor for injection, or in the form of lyophilized powders.

The pharmaceutical compositions according to the invention can alsocontain any pharmaceutically acceptable carrier. “Pharmaceuticallyacceptable carrier” as used herein refers to a pharmaceuticallyacceptable material, composition, or vehicle that is involved incarrying or transporting a compound of interest from one tissue, organ,or portion of the body to another tissue, organ, or portion of the body.For example, the carrier may be a liquid or solid filler, diluent,excipient, solvent, or encapsulating material, or a combination thereof.Each component of the carrier must be “pharmaceutically acceptable” inthat it must be compatible with the other ingredients of theformulation. It must also be suitable for use in contact with anytissues or organs with which it may come in contact, meaning that itmust not carry a risk of toxicity, irritation, allergic response,immunogenicity, or any other complication that excessively outweighs itstherapeutic benefits.

The pharmaceutical compositions according to the invention can also beencapsulated, tableted or prepared in an emulsion or syrup for oraladministration. Pharmaceutically acceptable solid or liquid carriers maybe added to enhance or stabilize the composition, or to facilitatepreparation of the composition. Liquid carriers include syrup, peanutoil, olive oil, glycerin, saline, alcohols and water. Solid carriersinclude starch, lactose, calcium sulfate, dihydrate, terra alba,magnesium stearate or stearic acid, talc, pectin, acacia, agar orgelatin. The carrier may also include a sustained release material suchas glyceryl monostearate or glyceryl distearate, alone or with a wax.

The pharmaceutical preparations are made following the conventionaltechniques of pharmacy involving milling, mixing, granulating, andcompressing, when necessary, for tablet forms; or milling, mixing andfilling for producing hard gelatin capsule forms. When a liquid carrieris used, the preparation will be in the form of a syrup, elixir,emulsion or an aqueous or non-aqueous suspension. Such a liquidformulation may be administered directly p.o. or filled into a softgelatin capsule.

The pharmaceutical compositions according to the invention may bedelivered in a therapeutically effective amount. The precisetherapeutically effective amount is that amount of the composition thatwill yield the most effective results in terms of efficacy of treatmentin a given subject. This amount will vary depending upon a variety offactors, including but not limited to, the characteristics of thetherapeutic compound (including activity, pharmacokinetics,pharmacodynamics, and bioavailability), the physiological condition ofthe subject (including age, sex, disease type and stage, generalphysical condition, responsiveness to a given dosage, and type ofmedication), the nature of the pharmaceutically acceptable carrier orcarriers in the formulation, and the route of administration. Oneskilled in the clinical and pharmacological arts will be able todetermine a therapeutically effective amount through routineexperimentation, for instance, by monitoring a subject's response toadministration of a compound and adjusting the dosage accordingly. Foradditional guidance, see Remington: The Science and Practice of Pharmacy(Gennaro ed. 20th edition, Williams & Wilkins Pa., USA) (2000).

Typical dosages of an effective amount of a GLP-1 receptor agonist or anincretin mimetic, particularly exenatide, may be about 5 micrograms(mcg) to 10 mcg and may be given subcutaneously twice per day. Dosagesmay also be about 10 mcg to about 20 mcg. The dosages may also be givenonly once per day or more than twice per day. Dosages can also be in theranges recommended by the manufacturer where known therapeutic compoundsare used, and also as indicated to the skilled artisan by the in vitroresponses or responses in animal models. Currently, exenatide ismarketed as BYETTA® exenatide injection by Amylin Pharmaceuticals. Inone embodiment, exenatide may be administered in accordance with theguidelines provided by Amylin Pharmaceuticals for BYETTA® exenatideinjection. For example, it may be initiated at 5 mcg per dose andadministered twice daily at anytime within a 60 minute period before themorning and evening meals. It may be increased to 10 mcg twice dailyafter one month of therapy. For further guidance, the full prescribinginformation for BYETTA® exenatide injection is available from Eli Lillyand Company. While, BYETTA® exenatide injection is administered viainjection, other forms of administration as described above are includedin the scope of the present invention. Dosages can typically be reducedby up to about one order of magnitude in concentration or amount withoutlosing the relevant biological activity. Thus, the actual dosage maydepend upon the judgment of the physician, the condition of the patient,and the effectiveness of the therapeutic method based, for example, onthe in vitro responsiveness of the relevant primary cultured cells orhistocultured tissue sample, such as biopsied malignant tumors, or theresponses observed in the appropriate animal models, as previouslydescribed.

The present invention is also directed to kits to treat short bowelsyndrome and/or spastic or hyperactive esophageal motor disorders (e.g.,esophageal spasms, nutcracker esophagus and achalasia) in a subject inneed thereof. The kit is useful for practicing the inventive method oftreating short bowel syndrome and/or spastic or hyperactive esophagealmotor disorders. The kits include an assemblage of materials orcomponents, including at least one of the inventive compositions. Thus,in some embodiments the kit contains a composition including a GLP-1receptor agonist or an incretin mimetic, particularly exenatide, or apolypeptide as described above.

The exact nature of the components configured in the inventive kitdepends on its intended purpose. For example, some embodiments areconfigured for the purpose of treating short bowel syndrome in a subjectin need thereof. In other embodiments, the kit is configured for thepurpose of treating spastic or hyperactive esophageal motor disorders.In one embodiment, the kit is configured particularly for the purpose oftreating mammalian subjects. In another embodiment, the kit isconfigured particularly for the purpose of treating human subjects. Infurther embodiments, the kit is configured for veterinary applications,treating subjects such as, but not limited to, farm animals, domesticanimals, and laboratory animals.

Instructions for use may be included in the kit. “Instructions for use”typically include a tangible expression describing the technique to beemployed in using the components of the kit to effect a desired outcome,such as to alleviate symptoms related to short bowel syndrome, to treatshort bowel syndrome, to alleviate symptoms related to spastic orhyperactive esophageal motor disorders, or to treat spastic orhyperactive esophageal motor disorders. Optionally, the kit alsocontains other useful components such as diluents, buffers,pharmaceutically acceptable carriers, syringes, catheters, applicators,pipetting or measuring tools, bandaging materials or other usefulparaphernalia as will be readily recognized by those of skill in theart.

The materials or components assembled in the kit can be provided to thepractitioner stored in any convenient and suitable ways that preservetheir operability and utility. For example, the components can be indissolved, dehydrated, or lyophilized form; they can be provided atroom, refrigerated or frozen temperatures. The components are typicallycontained in suitable packaging material(s). As employed herein, thephrase “packaging material” refers to one or more physical structuresused to house the contents of the kit, such as inventive compositionsand the like. The packaging material is constructed by well knownmethods, preferably to provide a sterile, contaminant-free environment.The packaging materials employed in the kit are those customarilyutilized in treatment of intestinal diseases or injection-typetherapies. As used herein, the term “package” refers to a suitable solidmatrix or material such as glass, plastic, paper, foil, and the like,capable of holding the individual kit components. Thus, for example, apackage can be a syringe used to contain suitable quantities of aninventive composition containing a GLP-1 receptor agonist, an incretinmimetic or particularly, exenatide. The packaging material generally hasan external label which indicates the contents and/or purpose of the kitand/or its components.

EXAMPLES

The following examples are provided to better illustrate the claimedinvention and are not to be interpreted as limiting the scope of theinvention. To the extent that specific materials are mentioned, it ismerely for purposes of illustration and is not intended to limit theinvention. One skilled in the art may develop equivalent means orreactants without the exercise of inventive capacity and withoutdeparting from the scope of the invention.

Example 1

A patient was on total parenteral nutrition with only two feet of smallbowel. Typically, less than three feet of small bowel is too little tosurvive on food alone. The patient was having nutritional compromise. Hewould experience diarrhea within 15 minutes of eating. Normal eatinghabits resulted in experiencing more than 10 bowel movements a day.Without the i.v. feedings, he would lose ten pounds in one week due todehydration. In July 2006, the patient was administered Byetta®exenatide and on the same day of administration, he did not experience abowel movement until six hours after a meal. Since the commencement oftreatment with Byetta® exenatide, he has not required i.v. feeding andexperiences 1-2 solid bowel movements a day. The patient's bowel healthreturned to normal and returned to work within one week of startingtreatment with Byetta® exenatide. The patient's nutritional statusimproved dramatically and has normalized. The patient has been usingByetta® exenatide since July 2006.

Example 2

Short bowel syndrome (SBS) subjects were selected based on clinicalsymptoms and history of greater than 50% distal small bowel resection.Before beginning exenatide treatment, each patient completed aquestionnaire documenting stool frequency and consistency. In addition,SBS symptoms, CBC, chemistries and BMI were also obtained. Anantroduodenal manometry study was performed during fasting, afterexenatide, and after a subsequent test meal. Each patient was thenstarted on exenatide 5 to 10 mcg subcutaneously twice a day. Over thefollowing month the parameters measured at baseline were repeated.

Example 3

The subjects consisted of 4 males and 1 female, ages 46 to 69 (mean:57.2). At baseline, all patients had severe diarrhea that ranged from 7to 15 bowel movements per day, often occurring within 15 minutes ofeating. After exenatide treatment, all 5 patients had an immediateimprovement in bowel frequency and form. In the most severely affectedpatient, the bowel movements reduced from 15 watery bowel movements perday to 2-3 formed stool. In all subjects, bowel movements were no longermeal related and often occurred hours after any meal. At baselinenutritional parameters were stable due to total parenteral nutrition(TPN) in most cases (n=3). However, after exenatide treatment, all 3patients no longer needed TPN. Despite the lack of TPN, no weight lossor biochemical nutritional deterioration was observed in any case.Previous attempts at ceasing TPN had resulted in immediate andlife-threatening dehydraton and malnutrition. Using normal bowelfunction as a goal, subjects described their improvement with exenatidetreatment as 65-100% improved. Antroduodenal manometry in 2 out of 5subjects demonstrated continuous low amplitude gastric contractionsduring fasting which completely normalized after exenatide.

Example 4

A patient was administered Byetta® exenatide. A catheter was placed inthe esophagus and esophageal contraction amplitudes were reduced.

Various embodiments of the invention are described above in the DetailedDescription. While these descriptions directly describe the aboveembodiments, it is understood that those skilled in the art may conceivemodifications and/or variations to the specific embodiments shown anddescribed herein. Any such modifications or variations that fall withinthe purview of this description are intended to be included therein aswell. Unless specifically noted, it is the intention of the inventorsthat the words and phrases in the specification and claims be given theordinary and accustomed meanings to those of ordinary skill in theapplicable art(s).

The foregoing description of various embodiments of the invention knownto the applicant at this time of filing the application has beenpresented and is intended for the purposes of illustration anddescription. The present description is not intended to be exhaustivenor limit the invention to the precise form disclosed and manymodifications and variations are possible in the light of the aboveteachings. The embodiments described serve to explain the principles ofthe invention and its practical application and to enable others skilledin the art to utilize the invention in various embodiments and withvarious modifications as are suited to the particular use contemplated.Therefore, it is intended that the invention not be limited to theparticular embodiments disclosed for carrying out the invention.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art that,based upon the teachings herein, changes and modifications may be madewithout departing from this invention and its broader aspects and,therefore, the appended claims are to encompass within their scope allsuch changes and modifications as are within the true spirit and scopeof this invention. It will be understood by those within the art that,in general, terms used herein are generally intended as “open” terms(e.g., the term “including” should be interpreted as “including but notlimited to,” the term “having” should be interpreted as “having atleast,” the term “includes” should be interpreted as “includes but isnot limited to,” etc.).

1. A method for treating short bowel syndrome in a subject in needthereof, comprising: providing a composition comprising exendin-4 (SEQID NO:3), a fragment of exendin-4 having the sequence disclosed by SEQID NO: 4, a fragment of exendin-4 having the sequence disclosed by SEQID NO: 5, exenatide (SEQ ID NO: 1), or combinations thereof, and apharmaceutically acceptable excipient or carrier; and administering atherapeutically effective amount of the composition to the subject totreat the short bowel syndrome.
 2. The method of claim 1, wherein thecomposition comprises exenatide and the pharmaceutically acceptableexcipient or carrier.
 3. The method of claim 1, wherein thetherapeutically effective amount is about 5 micrograms (mcg) to about 10mcg.
 4. The method of claim 1, wherein administering comprisesadministering the therapeutically effective amount twice per day.
 5. Themethod of claim 1, wherein the composition comprises exendin-4 (SEQ IDNO:3) and the pharmaceutically acceptable excipient or carrier.
 6. Themethod of claim 1, wherein the composition comprises the fragment ofexendin-4 having the sequence disclosed by SEQ ID NO: 4 and thepharmaceutically acceptable excipient or carrier.
 7. The method of claim1, wherein the composition comprises the fragment of exendin-4 havingthe sequence disclosed by SEQ ID NO: 5 and the pharmaceuticallyacceptable excipient or carrier.
 8. The method of claim 1, wherein thecomposition comprises a combination of the exendin-4 (SEQ ID NO:3),fragment of exendin-4 having the sequence disclosed by SEQ ID NO: 4,fragment of exendin-4 having the sequence disclosed by SEQ ID NO: 5, andexenatide (SEQ ID NO: 1), and the pharmaceutically acceptable excipientor carrier.
 9. A method of normalizing bowel function in a subjecthaving short bowel syndrome in need thereof, comprising: providing acomposition comprising an exendin-4 (SEQ ID NO:3), a fragment ofexendin-4 having the sequence disclosed by SEQ ID NO: 4, a fragment ofexendin-4 having the sequence disclosed by SEQ ID NO: 5, exenatide (SEQID NO: 1), or combinations thereof, and a pharmaceutically acceptableexcipient or carrier; and administering a therapeutically effectiveamount of the composition to the subject to normalize bowel function.10. The method of claim 9, wherein normalizing bowel function comprisesreducing the number of bowel movements in the subject.
 11. The method ofclaim 9, wherein the composition comprises exenatide and thepharmaceutically acceptable excipient or carrier.
 12. The method ofclaim 9, wherein the therapeutically effective amount is about 5micrograms (mcg) to about 10 mcg.
 13. The method of claim 9, whereinadministering comprises administering the therapeutically effectiveamount twice per day.
 14. The method of claim 9, wherein the compositioncomprises exendin-4 (SEQ ID NO:3) and the pharmaceutically acceptableexcipient or carrier.
 15. The method of claim 9, wherein the compositioncomprises the fragment of exendin-4 having the sequence disclosed by SEQID NO: 4 and the pharmaceutically acceptable excipient or carrier. 16.The method of claim 14, wherein the composition comprises the fragmentof exendin-4 having the sequence disclosed by SEQ ID NO: 5 and thepharmaceutically acceptable excipient or carrier.
 17. The method ofclaim 9, wherein the composition comprises a combination of theexendin-4 (SEQ ID NO:3), fragment of exendin-4 having the sequencedisclosed by SEQ ID NO: 4, fragment of exendin-4 having the sequencedisclosed by SEQ ID NO: 5, and exenatide (SEQ ID NO: 1), and thepharmaceutically acceptable excipient or carrier.